The TRP channels constitute a large and important class of channels involved in modulating cellular homeostatis. The channels are generally classified into six groups: TRPC (short), TRPV (vanilloid), TRPM (long, melastatin), TRPP (polycystins), TRPML (mucolipins), and TRPA (Ankyrin). The TRPC family has four groups TRPC1, TRPC4,5, TRPC3,6,7 and TRPC2; based on sequence homology and functional similarities. The TRPV family has 6 members, including TRPV5 and TRPV6, which are more closely related to each other than to TRPV1, TRPV2, TRPV3, and TRPV4. The TRPM family has 8 members, TRPMI (Melastatin or LTRPCI), TRPM3 (KIAA16I6 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(1), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (Trp-p8 or CMRI), TRPMS (Mtrl or LTRPC5), and TRPM4 (FLJ2004I or LTRPC4). The sole mammalian member of the TRPA family is ANKTM1, also known as TRPA1. TRPA1 is most closely related to TRPV3, and is more closely related to TRPV1 and TRPV2 than to TRPV5 and TRPV6. The TRPML family include TRPMLI (mucolipins 1), TRPML2 (mucolipins 2), and TRPML3 (mucolipin3). The TRPP family contains two groups of channels, those believed to have six trans-membrane domains (TRPP2 (PKD2), TRPP3 (PKD2L1), TRPP5 (PKD2L2)) and those that have 11 (TRPPI (PKDI, PC I), PKD-REJ and PKD-1 LI).
TRPA1 is a non-selective cation channel and is the sole mammalian member that defines the TRPA subfamily. In addition to calcium, ions, TRPA1 channels are permeable to other cations, for example sodium and Zinc. Thus, TRPA1 channels modulate membrane potential by modulating the flux of cations. Although non-selective cation channels such as TRPA1 modulate, among other things, calcium ion flux, they are mechanistically distinct from voltage-gated calcium channels. Voltage-gated calcium channels generally respond to depolarization of the potential difference across the membrane and can open to permit an influx of calcium from the extracellular medium and a rapid increase in intracellular calcium levels or concentrations. However, non-selective cation channels are generally signal transduction gated, long lasting, and produce less rapid changes in ion concentration. These mechanistic differences are accompanied by structural differences among voltage-gated and cation permeable channels. Thus, it is important to recognize the significant structural, functional, and mechanistic differences among different classes of ion channels even though many of the diverse channels act to regulate ion flux and membrane potential in various cell types and in response to numerous stimuli.
TRPA1 was shown to be highly expressed in dorsal root, trigeminal, and nodose ganglia in a specific subpopulation of neurons coexpressing another transient receptor potential family member, TRPV1, and in the hair cells of the inner ear (See Corey D P, et al., Nature 2004, 432(7018):723-730; Diogenes A, et al., J Dent Res 2007, 86(6):550-555; and Story G M, et al., Cell 2003, 112(6):819-829). After originally being characterized as a noxious cold-activated ion channel, several reports showed that TRPA1 can be activated by a large number of pungent or irritant compounds, such as cinnamaldehyde, AITC, acrolein, allicin, and formalin, all of which can induce acute pain, hyperalgesia, or neurogenic inflammation in animals and humans (See McNamara C R, et A, Proc Natl Acad Sci USA 2007, 104(33):13525-13530; Jordt S E, et al., Nature 2004, 427(6971):260-265; Macpherson 1-1, et al., Curr Biol 2005, 15(10):929-934; Macpherson L J, et al., J Neurosci 2007, 27(42):11412-11415; Namer B, et al., Neuroreport 2005, 16(9):955-959; and Ward L, et al., Pain 1996, 64(1):129-138). Additionally, these compounds have been shown to activate primary afferent nociceptors and enhance spontaneous and stimulus-evoked responses of spinal dorsal horn sensory neurons following peripheral application. More recently, the alpha, beta-unsaturated aldehyde, 4-hydroxy-2-nonenal (TINE) and the electrophilic carbon-containing PGJ2 metabolite, 15dPGJ2, released in response to tissue injury, inflammation, and oxidative stress, were reported to be the first endogenous activators of TRPA1 (Taylor-Clark T E, et al., Mol Pharmacol 2008, 73(2):274-281; and Trevisani M, et al., Proc. Natl. Acad Sci USA 2007, 104(33):13519-13524). It has also been reported that the majority of TRPA1 activators gate the channel through chemical reactivity of their electrophilic groups with some of the nucleophilic cysteine residues at the N-terminus of the channel and that TRPA1 can be gated through another mode of activation involving its N-terminal EF-hand calcium binding domain (Sec Hinman A, et al., Proc Natl Acad Sci USA 2006, 103(51):19564-19568; Macpherson L J, et al., Nature 2007, 445(7127):541-545). See also TRPA1 (Jordt et al. (2004) Nature 427:260-265; Bautista et al., (2005) PNAS: 102(34):12248-12252), WO2007073505, US2007219222, U.S. Pat. No. 5,369,094, and US2007196866.
The recent discoveries and descriptions of the transient receptor potential family of receptors, including TRPV1 and TRPA1, has provided a number of potential new therapeutic targets for treating chronic and acute pain, including acute formalin and CFA induced pain. Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients.